Prospective Neuroimaging in Huntington's Disease

项目主任/首席调查员(最后、第一、中间)：Rosas，Herminia Diana 摘要： 对有症状的亨廷顿病(HD)的实验治疗最重要的目标是 开发能够减缓病情发展的疾病修饰(神经保护)疗法。快速推进 基础和翻译研究已经确定了许多潜在的神经保护和 基于它们的治疗正在为临床试验创造一条不断扩大的管道。然而，临床试验 没有接近于跟上已经有一定理论基础的化合物，以及 安全和耐受性的可能性，而且差距正在迅速扩大。开发和使用 HD临床试验中的生物标志物具有深刻的潜力，可以提高HD的发生率和准确性 可以评估哪些化合物，也就是它们的目标。因为高清基本上是一种 进行性神经退行性疾病，神经成像措施作为直接的 疾病进展的衡量标准，也可能提供必要的敏感性和特异性 帮助评估第二阶段和第三阶段临床试验中的疾病修改。在目前的资助期间 期间，我们使用最先进的神经成像工具来显示HD患者的局部脑萎缩是早期的 进展性，与包括TFC在内的临床特征相对应。我们还将这些工具用作 大剂量肌酸的先导性研究中的药效学生物标志物 神经保护剂，用于HD患者。我们发现高剂量的肌酸延缓了脑萎缩， 氧化应激指标降低，可能减缓了认知能力的下降。我们正在寻求 在一项资助的安慰剂对照的双盲III期临床试验中验证我们的神经成像工具 大剂量肌酸作为疾病进展的生物标志物。肌酸是否应该减缓进展和 缓慢的脑萎缩，这将是展示神经成像作为一种 疾病修饰的药效学生物标志物。 PHS 398/2590(11/07版)页面续格式页面

Program Director/Principal Investigator (Last, First, Middle): Rosas, Herminia Diana Abstract: The most important goal of experimental therapeutics for symptomatic Huntington's disease (HD) is to develop disease-modifying (neuroprotective) therapies able to slow progression. Rapidly advancing basic and translational research has identified numerous potential targets for neuroprotection and treatments based on them are creating an expanding pipeline for clinical trials. However, clinical trials are not close to keeping up with compounds for which there is already some rationale, as well as likelihood of safety and tolerability, and the gap is quickly widening. The development and use of biomarkers in clinical trials for HD have profound potential to increase the rate and accuracy with which compounds, and by implication their targets, can be assessed. Since HD is fundamentally a progressive neurodegenerative disease, neuro-imaging measures hold great promise as direct measures of disease progression that may also provide the necessary sensitivity and specificity to help assess disease modification in Phase II and Phase III clinical trials. During the current funding period, we used state-of-the-art neuro-imaging tools to show that regional brain atrophy in HD is early and progressive, and corresponds to clinical features, including the TFC. We also used these tools as a pharmacodynamic biomarker in a pilot study of high-dose Creatine, a leading candidate neuroprotective agent, in HD subjects. We found that high dose Creatine slowed brain atrophy, reduced measures of oxidative stress, and may have slowed cognitive decline. We are seeking to validate our neuro-imaging tools in a funded placebo-controlled, double-blind Phase III clinical trial of high-dose creatine as a biomarker of disease progression. Should Creatine slow progression and slow brain atrophy, it will be a crucial step in demonstrating the value of neuro-imaging as a pharmacodynamic biomarker of disease modification. PHS 398/2590 (Rev. 11/07) Page Continuation Format Page